Survival After Recurrence of Ewing’s Sarcoma Family of Tumors
http://www.100md.com
《临床肿瘤学》
the University of Washington School of Medicine
Children’s Hospital and Regional Medical Center
Fred Hutchinson Cancer Research Center, Seattle, WA
ABSTRACT
PURPOSE: The overall survival (OS) of patients with relapsed Ewing’s sarcoma family of tumors (ESFT) is poor, and the relative benefit of high-dose therapy (HDT) is controversial.
PATIENTS AND METHODS: We retrospectively identified 55 consecutive ESFT patients with adequate medical records for review, who were treated at Children’s Hospital and Regional Medical Center and who developed disease recurrence between January 1, 1985 and December 31, 2002.
RESULTS: The median relapse-free interval (RFI) from diagnosis to first recurrence was 17 months (range, 5 to 90 months). Most recurrences were metastatic only (39 patients) or local and metastatic (10 patients). Twenty-seven patients (49%) achieved a partial or complete response to second-line treatment, with a median duration of response of 27 months (range, 5 to 119+ months). The 5-year OS rate for all relapsed patients was 23% (95% CI, 11% to 35%). By univariate analysis, improved OS was associated with response to second-line treatment versus no response (46% v 0%, respectively; P < .0001), RFI 24 months versus less than 24 months (48% v 12%, respectively; P = .0001), and no metastases at initial diagnosis versus presence of metastases (31% v 12%, respectively; P = .05). Because all 13 patients who received HDT also had responsive relapse, we performed a multivariate analysis. Reduced risk of death was associated with response to second-line therapy (relative risk, 0.14; 95% CI, 0.05 to 0.40), RFI 24 months (relative risk, 0.29; 95% CI, 0.13 to 0.66), and receiving HDT (relative risk, 0.26; 95% CI, 0.08 to 0.85).
CONCLUSION: HDT as consolidation therapy for relapsed ESFT seems to be associated with improved OS, even after adjusting for RFI and response to second-line treatment.
INTRODUCTION
The Ewing’s sarcoma family of tumors (ESFT) includes Ewing’s sarcoma of bone, extraosseous Ewing’s sarcoma, and peripheral neuroectodermal tumors of bone or soft tissue. Approximately 200 children and adolescents in the United States are diagnosed annually with ESFT.1,2 Multiagent chemotherapy, surgery, and radiation therapy have improved the progression-free survival (PFS) of newly diagnosed patients with localized disease to 60% to 70%,3-6 although the outcome for patients with metastatic disease at diagnosis remains poor, with a 18% to 30% PFS.6-8 Despite more intensive chemotherapy regimens and improved local control therapy, 30% to 40% of patients with ESFT experience disease recurrence.1,3-11 Patients with recurrent ESFT have an especially poor prognosis, with the likelihood of long-term survival of 20%,6,12-16 despite active conventional chemotherapy regimens for recurrent ESFT.17-19
The poor outcome for recurrent ESFT has led several investigators to use myeloablative or high-dose therapy (HDT), attempting to overcome relative but not absolute chemotherapy resistance.12,20-22 However, the role of HDT in the treatment of recurrent ESFT remains unproven. Many patients with recurrent ESFT are not candidates for HDT because of poor performance status or lack of response to second-line therapy. All studies using myeloablative therapy for recurrent ESFT exclude patients unable to receive myeloablative therapy.12,20-22 This creates selection bias favoring patients able to undergo HDT by excluding patients with especially aggressive or therapy-resistant disease. To control for selection bias, the outcome of recurrent ESFT patients should account for all patients, not just those receiving HDT. However, published comprehensive series of recurrent ESFT include few14,16 or no13,15 patients treated with HDT after recurrence. In addition, patients with initially metastatic ESFT have been excluded from most studies of recurrent ESFT.9,13,16 For these reasons, the role of myeloablative therapy in the treatment of recurrent ESFT remains controversial.
Since 1992, our institution has encouraged HDT as consolidation therapy for recurrent ESFT responsive to second-line treatment. To describe clinical characteristics and treatment strategies associated with relapsed ESFT, to identify prognostic factors associated with outcome of relapsed ESFT, and to address the role of HDT in recurrent ESFT, we reviewed our experience of patients with recurrent ESFT treated at Children’s Hospital and Regional Medical Center (CHRMC) from 1985 to 2002.
PATIENTS AND METHODS
Patients
Eligibility criteria for this retrospective review were as follows: diagnosis of ESFT; treatment at CHRMC (Seattle, WA) during any phase of therapy; and development of recurrent disease between January 1, 1985 and December 31, 2002. Patients were excluded if medical records were inadequate to characterize the clinical features and treatment at diagnosis or recurrence. All patients had biopsy-confirmed ESFT initially and received multiagent chemotherapy according to cooperative group studies or institutional pilot studies or standard therapy based on cooperative group trials. The most common initial therapies included vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE),3,22,23 VDC administered concomitantly with IE,24,25 VDC with dactinomycin,3,5 and VDC, dactinomycin, and methotrexate. In addition to chemotherapy, all patients received local control, which consisted of complete surgical excision alone, surgical excision followed by radiotherapy, or full-dose radiotherapy alone.
Relapse was detected radiographically, including bone scans for osseous sites, and confirmed by biopsy in all cases (except for patients with obvious recurrence treated with palliative therapy). Therapy after disease recurrence was variable but usually included multimodality treatment with chemotherapy, surgery, and radiotherapy. The most common chemotherapy regimens used at relapse were IE,18 IE in combination with carboplatin (ICE),19 and topotecan and cyclophosphamide (TC).16 Other chemotherapeutic agents used at relapse included topotecan alone,26 docetaxel,27 vinorelbine,28 and vincristine and dactinomycin.29 Patients treated with consolidation HDT received busulfan (Bu), melphalan (Mel), and thiotepa with or without total marrow irradiation (TMI) as previously reported.20 Age, sex, primary tumor site, sites of initial metastases, initial treatment regimen, relapse pattern, relapse treatment regimen, response to relapse treatment, and survival were reviewed for each patient. The CHRMC Institutional Review Board approved medical record review for this study.
Statistical Analysis
Statistical analyses of PFS and overall survival (OS) were performed using the Kaplan-Meier method for calculating survival curves and 95% CIs30 using SPSS version 10.0 statistical package (SPSS, Inc, Chicago, IL). Response to second-line therapy was defined as either partial or complete response as characterized in the medical record or radiographic reports. The original radiographic images were not reviewed to confirm the classification of response. Patients who were not classified as having partial or complete response were classified as nonresponders. Patients who did not respond to second-line therapy were considered to have a PFS of 0 months. For patients who did respond to relapse therapy, PFS was defined as the time from relapse to disease progression, death from any cause, or date of last contact. OS was defined as the time from initial recurrence to death from any cause. The initial relapse-free interval (RFI) was defined as the time from initial diagnosis to first progression. Differences in PFS and OS among groups defined by patient or treatment characteristics were analyzed using the log-rank test.31 Multivariate analysis of relative risks with 95% CI was performed with the Cox proportional hazards model.32 PFS and OS data were analyzed as of June 1, 2004.
RESULTS
Patient Characteristics and Treatment at Diagnosis
The clinical characteristics of 55 ESFT patients at initial diagnosis are listed in Table 1. The most common primary tumor sites were pelvis (33%) and femur (15%). Patients received a variety of initial chemotherapy regimens (Table 1). All patients received an alkylating agent (most commonly cyclophosphamide), all but one patient received doxorubicin, and all but one patient received vincristine. Sixty-two percent of patients received ifosfamide. Seventy-one percent of patients had surgery with (51%) or without (20%) radiation therapy for local therapy.
Patient Characteristics and Treatment at Initial Recurrence
The clinical features of patients at initial recurrence are listed in Table 2. The median initial RFI was 17 months (range, 5 to 90 months), with 80% of patients experiencing relapse off therapy. Seventy-one percent of patients developed metastatic (without local) recurrences, which were most commonly isolated distant bone (35%) or isolated lung (18%). Isolated local recurrences were uncommon, occurring in only 11% of patients. The treatment for recurrent disease was variable; most patients received either chemotherapy alone or chemotherapy with surgery and/or radiation therapy (78%). The most common chemotherapeutic regimens included IE (23 patients), ICE (six patients), and TC (seven patients). Patients who did not receive chemotherapy were treated with surgery and/or radiation therapy (9%) or palliative care only (13%). Only one patient treated without chemotherapy (surgery, radiotherapy, or palliative therapy only) achieved partial or complete response. The median survival time for patients who did not receive chemotherapy was 2 months (range, 0.5 to 36 months).
Factors Associated With PFS and OS for All Patients
For all patients with recurrent ESFT, the 5-year PFS rate was estimated to be 20% (95% CI, 9% to 31%), and the 5-year OS rate was estimated to be 23% (95% CI, 11% to 35%; Fig 1). Univariate analysis of potential prognostic factors (Table 3) demonstrated that improved PFS and OS were both associated with nonmetastatic disease at initial diagnosis (Fig 2) and with RFI 24 months (Fig 3). PFS and OS were strongly associated with response to second-line therapy versus no response (5-year PFS, 40% v 0%, respectively; OS, 46% v 0%, respectively; P < .0001). Overall, 49% of patients achieved partial or complete response to second-line treatment, with a median duration of response of 27 months (range, 5 to 119+ months). The median survival time for patients who responded to second-line treatment was 36 months (range, 8 to 119+ months). In contrast, the median survival time for patients who did not achieve a response to second-line treatment was 4 months (range, 0.5 to 18 months). Patients who received HDT for relapse had superior PFS and OS rates compared with patients who did not receive HDT for relapse (5-year PFS, 61% v 7%, respectively; P < .0001; OS, 77% v 7%, respectively; P < .0001). However, only patients who responded to second-line therapy received HDT (see multivariate analysis data in the following paragraph). Among patients who achieved a response to second-line therapy, PFS and OS were superior in patients who received HDT compared with patients who did not receive HDT (5-year PFS, 61% v 21%, respectively; P = .018; OS, 77% v 21%, respectively; P = .018; Fig 4). Except for one patient who experienced second recurrence, all patients have died. The cause of death in all but one patient was disease progression. One patient treated with surgery and chemotherapy but without HDT for first recurrence died of pneumonitis after receiving HDT as treatment for second recurrence. There was no significant difference in PFS or OS by age at initial diagnosis, sex, primary tumor site, or relapse on versus off initial therapy. Six patients with local only recurrence had 50% 5-year PFS and OS rates, which were not statistically different than patients with metastatic or combined sites of recurrence.
Clinical factors associated with improved PFS and OS were evaluated by multivariate analysis (Table 4). Response to second-line therapy, RFI more than 24 months, and receiving HDT all remained significantly associated with improved PFS and OS. Metastatic disease at initial diagnosis was not associated with worse outcome after controlling for response to second-line treatment (only seven of 25 patients with initially metastatic disease responded to second-line therapy compared with 20 of 30 patients with initially localized disease).
Clinical Features of Patients Treated With HDT After First Recurrence
The initial clinical features of the 13 patients who received HDT after first recurrence were similar to the whole study population (Tables 1 and 2). All patients received second-line chemotherapy (77% with surgery and radiotherapy and 23% with surgery only), and all patients achieved a response. Ten patients had complete surgical excision of all recurrent disease. Three patients had partial excision of recurrent disease. Two of these three patients also received radiotherapy. The median time between relapse and HDT was 5 months (range, 3 to 9 months). All patients received BuMelTT as HDT conditioning. Twelve patients received autologous, cryopreserved, unmodified peripheral-blood stem cells (PBSC), which were collected after second-line chemotherapy after HDT conditioning; one patient received syngeneic PBSC. PBSC collections were not evaluated for tumor contamination by molecular or immunocytochemical techniques. Nine patient had tandem HDT, with the second being TMI 10.5 to 15 Gy after recovery from BuMelTT, also with PBSC support. No patient died from HDT-related complications. Among the five patients who developed second recurrence after receiving HDT, the median time between first and second recurrence was 20 months (range, 11 to 54 months). Six of nine patients who received both BuMelTT and TMI are alive without recurrence (median time since first recurrence, 77 months; range, 60 to 90 months). Two of four patients who received BuMelTT only are alive without recurrence (27 and 78 months since first recurrence).
DISCUSSION
In contrast to the dramatic improvement in survival for newly diagnosed ESFT over the last 30 years, the prognosis after disease recurrence remains poor, especially for patients with RFI less than 24 months. Our single-institution experience confirms the poor overall outcome for recurrent ESFT patients. Similar to other series, we identified an association between improved OS and RFI 24 months6,14-16,33 and response to second-line therapy.13,16 Unlike most retrospective series for patients with recurrent ESFT, we evaluated the role of HDT using a multivariate analysis, controlling for RFI and response to second-line therapy. After adjusting for the other prognostic factors, the current study suggests that the use of HDT as consolidation therapy after recurrence of ESFT may be associated with improved OS.
Rodriguez-Galindo et al15 reported the St Jude Children’s Research Hospital experience from 1979 to 1999 with recurrent ESFT, in which no patient received HDT. As with other series, 5-year OS was poor (17.7%), and improved OS was associated with RFI more than 24 months. The most common second-line chemotherapy was ICE. There was no statistical difference in 5-year OS between patients treated with ICE (24%) compared with other chemotherapy regimens (16%). The majority of recurrent ESFT patients in this series had local recurrence, either isolated (35%) or combined local and distant (17%) recurrence. Combined local and distant relapse was associated with an inferior 5-year OS rate (13%) compared with local relapse only (22%) or distant relapse only (18%). The authors hypothesized that the routine use of radiotherapy alone for local control (especially radiotherapy doses < 35 Gy) may have contributed to the relatively high local failure rate. Aggressive surgery seemed to improve OS for patients who developed local recurrence. Because local failure is uncommon with primary surgical excision or higher dose radiotherapy for local control, it is not clear whether the results observed in this single-institution series apply to more contemporary recurrent ESFT patients. The absence of patients treated with HDT limit the comparison between this series and the current report.
Two other series have suggested a potential benefit with HDT for recurrent ESFT patients. Shankar et al14 reported increased duration of survival but no improvement in long-term event-free survival (EFS) for seven recurrent ESFT patients who received HDT compared with 57 patients treated without HDT. Active treatment rather than palliative care was associated with improved OS, as were prolonged RFI and relapse after the completion of initial therapy. The ultimate outcome was poor, even among favorable prognostic groups; the 5-year OS rate was 8% for patients receiving active treatment and less than 20% for patients with RFI more than 24 months. The authors concluded that aggressive therapy, including HDT, delayed but did not prevent death from recurrent ESFT. Bacci et al16 reported a series of 195 patients with recurrent ESFT, of whom 33 received BuMel HDT. By univariate analysis, improved 5-year EFS and months of survival were associated with RFI more than 24 months, treatment with multimodality therapy or complete surgical excision, isolated pulmonary recurrence, and treatment with HDT. Isolated distant relapse was associated with improved 5-year EFS but not with improved duration of survival compared with other patterns of recurrence. The 5-year OS rate for the study group was 13.8%. For patients with RFI more than 24 months or isolated pulmonary metastases, the 5-year OS rates were also poor (14.3% and 14.5%, respectively). Patients who received HDT had an improved 5-year EFS rate (21.2%) compared with patients who received standard-dose chemotherapy only (0%). However, a multivariate analysis was not performed to control for other prognostic factors.
The optimal myeloablative conditioning regimen for ESFT remains uncertain. Multiple regimens have been reported, most frequently with BuMel chemotherapy and often with total-body irradiation (TBI). A respective review of data reported to the European Bone Marrow Transplantation Solid Tumor Registry showed a trend towards improved EFS in patients who received BuMel compared with TBI-containing regimens.22 Burdach et al21 reported similar outcome with an earlier regimen containing TBI, Mel, and etoposide and a more recent tandem transplantation regimen including Mel and etoposide. Our institution has used BuMelTT conditioning for all patients with recurrent ESFT, as previously reported.20 Most of the patients in the current series also received TMI as a second myeloablative therapy. Because of the size of our series and the nonrandomized use of single or tandem HDT, we cannot determine whether the addition of TMI contributed to the OS seen in our patients treated with HDT. It is possible that similar results could be obtained with BuMelTT alone. Perentesis et al34 and Davies et al35 have used the identical BuMelTT regimen for poor prognosis (initially metastatic or recurrent) ESFT patients, also with encouraging early survival data.
The relative benefit of HDT over standard-dose chemotherapy in the treatment of ESFT also remains unclear. Using a historical control group, Burdach et al12 reported improved EFS for patients with initial metastatic or recurrent ESFT treated with TBI, Mel, and etoposide HDT compared with standard-dose chemotherapy. However, the potential for patient selection bias confounds the interpretation of single-arm HDT studies. A prospective, randomized comparison of HDT to standard-dose chemotherapy would provide more compelling evidence of benefit. On the basis of the promising European Bone Marrow Transplantation Solid Tumor Registry data, BuMel HDT as consolidation therapy is currently being compared with continued standard-dose chemotherapy for patients with isolated pulmonary metastases at initial diagnosis in the international EuroEWING 99 trial.36 EuroEWING 99 is the first randomized evaluation of the role of HDT for poor prognosis ESFT. However, EuroEWING 99 does not include a randomized evaluation of HDT for ESFT patients at highest risk for treatment failure (ie, those with bone or bone marrow metastases at diagnosis). Meyers et al37 and Kushner and Meyers38 have recently questioned the utility of HDT in ESFT patients with bone or bone marrow metastases. In a prospective study enrolling ESFT patients with bone or bone marrow metastases at initial diagnosis, consolidation with HDT (TBI, Mel, and etoposide) did not improve EFS compared with historical controls treated with standard-dose chemotherapy.37 In addition, the EFS rate was 5% for ESFT patients with initial bone or bone marrow metastases treated with HDT at the Memorial Sloan-Kettering Cancer Center.38 For this especially poor prognosis group of patients, the role of HDT remains particularly unproven.
Our single-institution review of outcome after recurrence of ESFT has several limitations. First, our sample size precludes the detection of small but clinically significant differences between prognostic groups and the ability to include more factors in a multivariate analysis. For example, we were unable to evaluate the prognostic significance of multiple osseous sites of recurrence or bone marrow as a site of relapse because of the limitations of sample size. Multiple bone or bone marrow metastases are associated with inferior outcome among patients with newly diagnosed metastatic ESFT.39 Second, retrospective abstraction of data from patient records potentially reduces the accuracy of information. For example, we could not distinguish between patients achieving complete versus partial response with certainty because of nonuniform reporting of radiographic response or unavailable radiographic images. By combining patients with either partial or complete response, we were unable to determine whether achieving a complete response was associated with improved outcome. Third, patients included in this series may differ from current ESFT patients. For example, ESFT patients who developed recurrence in 1985 to 1992 had not received ifosfamide in their initial therapy, although it is part of standard therapy now. Most patients in our series were treated with either IE or ICE as second-line chemotherapy, which are less likely to be effective in patients previously treated with IE. However, prior ifosfamide therapy was not associated with PFS or OS in our series (data not shown). Fourth, the apparent improvement in PFS and OS seen in patients treated with HDT may be a result of other factors. Before 1992, no recurrent ESFT patients (zero of 10 patients) who responded to second-line therapy received HDT. From 1992 and after, most patients (13 of 17 patients) who responded to second-line therapy received HDT. The rationale for omission of HDT in responding patients since 1992 included relapse between 1992 and 1995 before the use of HDT for responding patients was routine (two patients), isolated local recurrence in 1993 (one patient), and moderate to severe restrictive lung disease secondary to previous pulmonary radiotherapy (one patient). It is possible that some change (other than HDT) in the management of recurrent ESFT patients after 1992 accounts for the apparent improvement in outcome. Patients after 1992 may have received more aggressive second-line chemotherapy, surgery, and/or radiotherapy. For example, the availability of hematopoietic cytokine support since 1992 may have allowed intensification of second-line chemotherapy by preventing prolonged neutropenia. However, the most dramatic change in patient management seems to be the routine use of HDT for patients with responsive relapse. Finally, selection bias may still contribute to the apparent improvement in outcome with HDT, despite controlling for RFI and response to second-line therapy. For example, patients who responded to second-line therapy but who progressed again before HDT would be excluded from HDT. This would potentially select the most responsive patients for HDT. However, patients who responded to second-line therapy almost always had a response duration (median, 27 months; range, 8 to 119+ months) sufficient to plan and deliver HDT (median time from first recurrence to HDT, 5 months; range, 3 to 9 months). Therefore, it is unlikely that the delay between recurrence and HDT allowed selection of more favorable patients among those who responded to second-line therapy.
There are several barriers to improve the outcome for recurrent ESFT patients. First, improved outcome is clearly associated with response to second-line therapy, yet only 49% of patients respond. New strategies are needed to improve response in previously treated ESFT patients. Promising combination therapies include TC17 and gemcitabine and docetaxel.40 Second, innovative second-line treatment is especially needed for patients who experience recurrence after treatment for metastatic ESFT. In our series, only 28% of initially metastatic patients responded to second-line therapy compared with 67% of initially localized patients. Biologically targeted therapy, such as fenretinide,41 is a particularly attractive novel treatment strategy for recurrent ESFT. Third, the rationale for HDT and optimal myeloablative conditioning remain uncertain. In the absence of a randomized trial comparing HDT consolidation therapy to standard-dose chemotherapy for recurrent ESFT (or comparing different HDT regimens), the role for HDT will remain controversial. Finally, improved initial therapy could reduce disease recurrence and obviate the need for re-treatment. Both the Children’s Oncology Group and EuroEWING 99 are pursuing phase III studies of front-line therapy to improve the outcome for newly diagnosed ESFT.
Even with improved primary treatment for ESFT, recurrent disease remains a significant clinical problem for pediatric and medical oncologists. Our retrospective analysis confirms the poor overall outcome after relapse of ESFT reported by others. We observed improved PFS and OS in patients with prolonged RFI, a response to second-line therapy, initially nonmetastatic disease, and HDT as consolidation therapy. After controlling for RFI and response to second-line therapy, use of HDT seems to be an independent prognostic factor associated with PFS and OS. HDT consolidation for patients who respond to second-line therapy is a promising but unproven approach that may improve the outcome for recurrent ESFT. We concluded that further investigation of HDT, including the determination of the optimal conditioning regimen, is warranted in recurrent ESFT.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported in part by the Rex and Arlene Garrison Student Summer Fellowships from the American Cancer Society and National Institutes of Health grant No. CA-87721.
Presented in abstract form at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Children’s Hospital and Regional Medical Center
Fred Hutchinson Cancer Research Center, Seattle, WA
ABSTRACT
PURPOSE: The overall survival (OS) of patients with relapsed Ewing’s sarcoma family of tumors (ESFT) is poor, and the relative benefit of high-dose therapy (HDT) is controversial.
PATIENTS AND METHODS: We retrospectively identified 55 consecutive ESFT patients with adequate medical records for review, who were treated at Children’s Hospital and Regional Medical Center and who developed disease recurrence between January 1, 1985 and December 31, 2002.
RESULTS: The median relapse-free interval (RFI) from diagnosis to first recurrence was 17 months (range, 5 to 90 months). Most recurrences were metastatic only (39 patients) or local and metastatic (10 patients). Twenty-seven patients (49%) achieved a partial or complete response to second-line treatment, with a median duration of response of 27 months (range, 5 to 119+ months). The 5-year OS rate for all relapsed patients was 23% (95% CI, 11% to 35%). By univariate analysis, improved OS was associated with response to second-line treatment versus no response (46% v 0%, respectively; P < .0001), RFI 24 months versus less than 24 months (48% v 12%, respectively; P = .0001), and no metastases at initial diagnosis versus presence of metastases (31% v 12%, respectively; P = .05). Because all 13 patients who received HDT also had responsive relapse, we performed a multivariate analysis. Reduced risk of death was associated with response to second-line therapy (relative risk, 0.14; 95% CI, 0.05 to 0.40), RFI 24 months (relative risk, 0.29; 95% CI, 0.13 to 0.66), and receiving HDT (relative risk, 0.26; 95% CI, 0.08 to 0.85).
CONCLUSION: HDT as consolidation therapy for relapsed ESFT seems to be associated with improved OS, even after adjusting for RFI and response to second-line treatment.
INTRODUCTION
The Ewing’s sarcoma family of tumors (ESFT) includes Ewing’s sarcoma of bone, extraosseous Ewing’s sarcoma, and peripheral neuroectodermal tumors of bone or soft tissue. Approximately 200 children and adolescents in the United States are diagnosed annually with ESFT.1,2 Multiagent chemotherapy, surgery, and radiation therapy have improved the progression-free survival (PFS) of newly diagnosed patients with localized disease to 60% to 70%,3-6 although the outcome for patients with metastatic disease at diagnosis remains poor, with a 18% to 30% PFS.6-8 Despite more intensive chemotherapy regimens and improved local control therapy, 30% to 40% of patients with ESFT experience disease recurrence.1,3-11 Patients with recurrent ESFT have an especially poor prognosis, with the likelihood of long-term survival of 20%,6,12-16 despite active conventional chemotherapy regimens for recurrent ESFT.17-19
The poor outcome for recurrent ESFT has led several investigators to use myeloablative or high-dose therapy (HDT), attempting to overcome relative but not absolute chemotherapy resistance.12,20-22 However, the role of HDT in the treatment of recurrent ESFT remains unproven. Many patients with recurrent ESFT are not candidates for HDT because of poor performance status or lack of response to second-line therapy. All studies using myeloablative therapy for recurrent ESFT exclude patients unable to receive myeloablative therapy.12,20-22 This creates selection bias favoring patients able to undergo HDT by excluding patients with especially aggressive or therapy-resistant disease. To control for selection bias, the outcome of recurrent ESFT patients should account for all patients, not just those receiving HDT. However, published comprehensive series of recurrent ESFT include few14,16 or no13,15 patients treated with HDT after recurrence. In addition, patients with initially metastatic ESFT have been excluded from most studies of recurrent ESFT.9,13,16 For these reasons, the role of myeloablative therapy in the treatment of recurrent ESFT remains controversial.
Since 1992, our institution has encouraged HDT as consolidation therapy for recurrent ESFT responsive to second-line treatment. To describe clinical characteristics and treatment strategies associated with relapsed ESFT, to identify prognostic factors associated with outcome of relapsed ESFT, and to address the role of HDT in recurrent ESFT, we reviewed our experience of patients with recurrent ESFT treated at Children’s Hospital and Regional Medical Center (CHRMC) from 1985 to 2002.
PATIENTS AND METHODS
Patients
Eligibility criteria for this retrospective review were as follows: diagnosis of ESFT; treatment at CHRMC (Seattle, WA) during any phase of therapy; and development of recurrent disease between January 1, 1985 and December 31, 2002. Patients were excluded if medical records were inadequate to characterize the clinical features and treatment at diagnosis or recurrence. All patients had biopsy-confirmed ESFT initially and received multiagent chemotherapy according to cooperative group studies or institutional pilot studies or standard therapy based on cooperative group trials. The most common initial therapies included vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE),3,22,23 VDC administered concomitantly with IE,24,25 VDC with dactinomycin,3,5 and VDC, dactinomycin, and methotrexate. In addition to chemotherapy, all patients received local control, which consisted of complete surgical excision alone, surgical excision followed by radiotherapy, or full-dose radiotherapy alone.
Relapse was detected radiographically, including bone scans for osseous sites, and confirmed by biopsy in all cases (except for patients with obvious recurrence treated with palliative therapy). Therapy after disease recurrence was variable but usually included multimodality treatment with chemotherapy, surgery, and radiotherapy. The most common chemotherapy regimens used at relapse were IE,18 IE in combination with carboplatin (ICE),19 and topotecan and cyclophosphamide (TC).16 Other chemotherapeutic agents used at relapse included topotecan alone,26 docetaxel,27 vinorelbine,28 and vincristine and dactinomycin.29 Patients treated with consolidation HDT received busulfan (Bu), melphalan (Mel), and thiotepa with or without total marrow irradiation (TMI) as previously reported.20 Age, sex, primary tumor site, sites of initial metastases, initial treatment regimen, relapse pattern, relapse treatment regimen, response to relapse treatment, and survival were reviewed for each patient. The CHRMC Institutional Review Board approved medical record review for this study.
Statistical Analysis
Statistical analyses of PFS and overall survival (OS) were performed using the Kaplan-Meier method for calculating survival curves and 95% CIs30 using SPSS version 10.0 statistical package (SPSS, Inc, Chicago, IL). Response to second-line therapy was defined as either partial or complete response as characterized in the medical record or radiographic reports. The original radiographic images were not reviewed to confirm the classification of response. Patients who were not classified as having partial or complete response were classified as nonresponders. Patients who did not respond to second-line therapy were considered to have a PFS of 0 months. For patients who did respond to relapse therapy, PFS was defined as the time from relapse to disease progression, death from any cause, or date of last contact. OS was defined as the time from initial recurrence to death from any cause. The initial relapse-free interval (RFI) was defined as the time from initial diagnosis to first progression. Differences in PFS and OS among groups defined by patient or treatment characteristics were analyzed using the log-rank test.31 Multivariate analysis of relative risks with 95% CI was performed with the Cox proportional hazards model.32 PFS and OS data were analyzed as of June 1, 2004.
RESULTS
Patient Characteristics and Treatment at Diagnosis
The clinical characteristics of 55 ESFT patients at initial diagnosis are listed in Table 1. The most common primary tumor sites were pelvis (33%) and femur (15%). Patients received a variety of initial chemotherapy regimens (Table 1). All patients received an alkylating agent (most commonly cyclophosphamide), all but one patient received doxorubicin, and all but one patient received vincristine. Sixty-two percent of patients received ifosfamide. Seventy-one percent of patients had surgery with (51%) or without (20%) radiation therapy for local therapy.
Patient Characteristics and Treatment at Initial Recurrence
The clinical features of patients at initial recurrence are listed in Table 2. The median initial RFI was 17 months (range, 5 to 90 months), with 80% of patients experiencing relapse off therapy. Seventy-one percent of patients developed metastatic (without local) recurrences, which were most commonly isolated distant bone (35%) or isolated lung (18%). Isolated local recurrences were uncommon, occurring in only 11% of patients. The treatment for recurrent disease was variable; most patients received either chemotherapy alone or chemotherapy with surgery and/or radiation therapy (78%). The most common chemotherapeutic regimens included IE (23 patients), ICE (six patients), and TC (seven patients). Patients who did not receive chemotherapy were treated with surgery and/or radiation therapy (9%) or palliative care only (13%). Only one patient treated without chemotherapy (surgery, radiotherapy, or palliative therapy only) achieved partial or complete response. The median survival time for patients who did not receive chemotherapy was 2 months (range, 0.5 to 36 months).
Factors Associated With PFS and OS for All Patients
For all patients with recurrent ESFT, the 5-year PFS rate was estimated to be 20% (95% CI, 9% to 31%), and the 5-year OS rate was estimated to be 23% (95% CI, 11% to 35%; Fig 1). Univariate analysis of potential prognostic factors (Table 3) demonstrated that improved PFS and OS were both associated with nonmetastatic disease at initial diagnosis (Fig 2) and with RFI 24 months (Fig 3). PFS and OS were strongly associated with response to second-line therapy versus no response (5-year PFS, 40% v 0%, respectively; OS, 46% v 0%, respectively; P < .0001). Overall, 49% of patients achieved partial or complete response to second-line treatment, with a median duration of response of 27 months (range, 5 to 119+ months). The median survival time for patients who responded to second-line treatment was 36 months (range, 8 to 119+ months). In contrast, the median survival time for patients who did not achieve a response to second-line treatment was 4 months (range, 0.5 to 18 months). Patients who received HDT for relapse had superior PFS and OS rates compared with patients who did not receive HDT for relapse (5-year PFS, 61% v 7%, respectively; P < .0001; OS, 77% v 7%, respectively; P < .0001). However, only patients who responded to second-line therapy received HDT (see multivariate analysis data in the following paragraph). Among patients who achieved a response to second-line therapy, PFS and OS were superior in patients who received HDT compared with patients who did not receive HDT (5-year PFS, 61% v 21%, respectively; P = .018; OS, 77% v 21%, respectively; P = .018; Fig 4). Except for one patient who experienced second recurrence, all patients have died. The cause of death in all but one patient was disease progression. One patient treated with surgery and chemotherapy but without HDT for first recurrence died of pneumonitis after receiving HDT as treatment for second recurrence. There was no significant difference in PFS or OS by age at initial diagnosis, sex, primary tumor site, or relapse on versus off initial therapy. Six patients with local only recurrence had 50% 5-year PFS and OS rates, which were not statistically different than patients with metastatic or combined sites of recurrence.
Clinical factors associated with improved PFS and OS were evaluated by multivariate analysis (Table 4). Response to second-line therapy, RFI more than 24 months, and receiving HDT all remained significantly associated with improved PFS and OS. Metastatic disease at initial diagnosis was not associated with worse outcome after controlling for response to second-line treatment (only seven of 25 patients with initially metastatic disease responded to second-line therapy compared with 20 of 30 patients with initially localized disease).
Clinical Features of Patients Treated With HDT After First Recurrence
The initial clinical features of the 13 patients who received HDT after first recurrence were similar to the whole study population (Tables 1 and 2). All patients received second-line chemotherapy (77% with surgery and radiotherapy and 23% with surgery only), and all patients achieved a response. Ten patients had complete surgical excision of all recurrent disease. Three patients had partial excision of recurrent disease. Two of these three patients also received radiotherapy. The median time between relapse and HDT was 5 months (range, 3 to 9 months). All patients received BuMelTT as HDT conditioning. Twelve patients received autologous, cryopreserved, unmodified peripheral-blood stem cells (PBSC), which were collected after second-line chemotherapy after HDT conditioning; one patient received syngeneic PBSC. PBSC collections were not evaluated for tumor contamination by molecular or immunocytochemical techniques. Nine patient had tandem HDT, with the second being TMI 10.5 to 15 Gy after recovery from BuMelTT, also with PBSC support. No patient died from HDT-related complications. Among the five patients who developed second recurrence after receiving HDT, the median time between first and second recurrence was 20 months (range, 11 to 54 months). Six of nine patients who received both BuMelTT and TMI are alive without recurrence (median time since first recurrence, 77 months; range, 60 to 90 months). Two of four patients who received BuMelTT only are alive without recurrence (27 and 78 months since first recurrence).
DISCUSSION
In contrast to the dramatic improvement in survival for newly diagnosed ESFT over the last 30 years, the prognosis after disease recurrence remains poor, especially for patients with RFI less than 24 months. Our single-institution experience confirms the poor overall outcome for recurrent ESFT patients. Similar to other series, we identified an association between improved OS and RFI 24 months6,14-16,33 and response to second-line therapy.13,16 Unlike most retrospective series for patients with recurrent ESFT, we evaluated the role of HDT using a multivariate analysis, controlling for RFI and response to second-line therapy. After adjusting for the other prognostic factors, the current study suggests that the use of HDT as consolidation therapy after recurrence of ESFT may be associated with improved OS.
Rodriguez-Galindo et al15 reported the St Jude Children’s Research Hospital experience from 1979 to 1999 with recurrent ESFT, in which no patient received HDT. As with other series, 5-year OS was poor (17.7%), and improved OS was associated with RFI more than 24 months. The most common second-line chemotherapy was ICE. There was no statistical difference in 5-year OS between patients treated with ICE (24%) compared with other chemotherapy regimens (16%). The majority of recurrent ESFT patients in this series had local recurrence, either isolated (35%) or combined local and distant (17%) recurrence. Combined local and distant relapse was associated with an inferior 5-year OS rate (13%) compared with local relapse only (22%) or distant relapse only (18%). The authors hypothesized that the routine use of radiotherapy alone for local control (especially radiotherapy doses < 35 Gy) may have contributed to the relatively high local failure rate. Aggressive surgery seemed to improve OS for patients who developed local recurrence. Because local failure is uncommon with primary surgical excision or higher dose radiotherapy for local control, it is not clear whether the results observed in this single-institution series apply to more contemporary recurrent ESFT patients. The absence of patients treated with HDT limit the comparison between this series and the current report.
Two other series have suggested a potential benefit with HDT for recurrent ESFT patients. Shankar et al14 reported increased duration of survival but no improvement in long-term event-free survival (EFS) for seven recurrent ESFT patients who received HDT compared with 57 patients treated without HDT. Active treatment rather than palliative care was associated with improved OS, as were prolonged RFI and relapse after the completion of initial therapy. The ultimate outcome was poor, even among favorable prognostic groups; the 5-year OS rate was 8% for patients receiving active treatment and less than 20% for patients with RFI more than 24 months. The authors concluded that aggressive therapy, including HDT, delayed but did not prevent death from recurrent ESFT. Bacci et al16 reported a series of 195 patients with recurrent ESFT, of whom 33 received BuMel HDT. By univariate analysis, improved 5-year EFS and months of survival were associated with RFI more than 24 months, treatment with multimodality therapy or complete surgical excision, isolated pulmonary recurrence, and treatment with HDT. Isolated distant relapse was associated with improved 5-year EFS but not with improved duration of survival compared with other patterns of recurrence. The 5-year OS rate for the study group was 13.8%. For patients with RFI more than 24 months or isolated pulmonary metastases, the 5-year OS rates were also poor (14.3% and 14.5%, respectively). Patients who received HDT had an improved 5-year EFS rate (21.2%) compared with patients who received standard-dose chemotherapy only (0%). However, a multivariate analysis was not performed to control for other prognostic factors.
The optimal myeloablative conditioning regimen for ESFT remains uncertain. Multiple regimens have been reported, most frequently with BuMel chemotherapy and often with total-body irradiation (TBI). A respective review of data reported to the European Bone Marrow Transplantation Solid Tumor Registry showed a trend towards improved EFS in patients who received BuMel compared with TBI-containing regimens.22 Burdach et al21 reported similar outcome with an earlier regimen containing TBI, Mel, and etoposide and a more recent tandem transplantation regimen including Mel and etoposide. Our institution has used BuMelTT conditioning for all patients with recurrent ESFT, as previously reported.20 Most of the patients in the current series also received TMI as a second myeloablative therapy. Because of the size of our series and the nonrandomized use of single or tandem HDT, we cannot determine whether the addition of TMI contributed to the OS seen in our patients treated with HDT. It is possible that similar results could be obtained with BuMelTT alone. Perentesis et al34 and Davies et al35 have used the identical BuMelTT regimen for poor prognosis (initially metastatic or recurrent) ESFT patients, also with encouraging early survival data.
The relative benefit of HDT over standard-dose chemotherapy in the treatment of ESFT also remains unclear. Using a historical control group, Burdach et al12 reported improved EFS for patients with initial metastatic or recurrent ESFT treated with TBI, Mel, and etoposide HDT compared with standard-dose chemotherapy. However, the potential for patient selection bias confounds the interpretation of single-arm HDT studies. A prospective, randomized comparison of HDT to standard-dose chemotherapy would provide more compelling evidence of benefit. On the basis of the promising European Bone Marrow Transplantation Solid Tumor Registry data, BuMel HDT as consolidation therapy is currently being compared with continued standard-dose chemotherapy for patients with isolated pulmonary metastases at initial diagnosis in the international EuroEWING 99 trial.36 EuroEWING 99 is the first randomized evaluation of the role of HDT for poor prognosis ESFT. However, EuroEWING 99 does not include a randomized evaluation of HDT for ESFT patients at highest risk for treatment failure (ie, those with bone or bone marrow metastases at diagnosis). Meyers et al37 and Kushner and Meyers38 have recently questioned the utility of HDT in ESFT patients with bone or bone marrow metastases. In a prospective study enrolling ESFT patients with bone or bone marrow metastases at initial diagnosis, consolidation with HDT (TBI, Mel, and etoposide) did not improve EFS compared with historical controls treated with standard-dose chemotherapy.37 In addition, the EFS rate was 5% for ESFT patients with initial bone or bone marrow metastases treated with HDT at the Memorial Sloan-Kettering Cancer Center.38 For this especially poor prognosis group of patients, the role of HDT remains particularly unproven.
Our single-institution review of outcome after recurrence of ESFT has several limitations. First, our sample size precludes the detection of small but clinically significant differences between prognostic groups and the ability to include more factors in a multivariate analysis. For example, we were unable to evaluate the prognostic significance of multiple osseous sites of recurrence or bone marrow as a site of relapse because of the limitations of sample size. Multiple bone or bone marrow metastases are associated with inferior outcome among patients with newly diagnosed metastatic ESFT.39 Second, retrospective abstraction of data from patient records potentially reduces the accuracy of information. For example, we could not distinguish between patients achieving complete versus partial response with certainty because of nonuniform reporting of radiographic response or unavailable radiographic images. By combining patients with either partial or complete response, we were unable to determine whether achieving a complete response was associated with improved outcome. Third, patients included in this series may differ from current ESFT patients. For example, ESFT patients who developed recurrence in 1985 to 1992 had not received ifosfamide in their initial therapy, although it is part of standard therapy now. Most patients in our series were treated with either IE or ICE as second-line chemotherapy, which are less likely to be effective in patients previously treated with IE. However, prior ifosfamide therapy was not associated with PFS or OS in our series (data not shown). Fourth, the apparent improvement in PFS and OS seen in patients treated with HDT may be a result of other factors. Before 1992, no recurrent ESFT patients (zero of 10 patients) who responded to second-line therapy received HDT. From 1992 and after, most patients (13 of 17 patients) who responded to second-line therapy received HDT. The rationale for omission of HDT in responding patients since 1992 included relapse between 1992 and 1995 before the use of HDT for responding patients was routine (two patients), isolated local recurrence in 1993 (one patient), and moderate to severe restrictive lung disease secondary to previous pulmonary radiotherapy (one patient). It is possible that some change (other than HDT) in the management of recurrent ESFT patients after 1992 accounts for the apparent improvement in outcome. Patients after 1992 may have received more aggressive second-line chemotherapy, surgery, and/or radiotherapy. For example, the availability of hematopoietic cytokine support since 1992 may have allowed intensification of second-line chemotherapy by preventing prolonged neutropenia. However, the most dramatic change in patient management seems to be the routine use of HDT for patients with responsive relapse. Finally, selection bias may still contribute to the apparent improvement in outcome with HDT, despite controlling for RFI and response to second-line therapy. For example, patients who responded to second-line therapy but who progressed again before HDT would be excluded from HDT. This would potentially select the most responsive patients for HDT. However, patients who responded to second-line therapy almost always had a response duration (median, 27 months; range, 8 to 119+ months) sufficient to plan and deliver HDT (median time from first recurrence to HDT, 5 months; range, 3 to 9 months). Therefore, it is unlikely that the delay between recurrence and HDT allowed selection of more favorable patients among those who responded to second-line therapy.
There are several barriers to improve the outcome for recurrent ESFT patients. First, improved outcome is clearly associated with response to second-line therapy, yet only 49% of patients respond. New strategies are needed to improve response in previously treated ESFT patients. Promising combination therapies include TC17 and gemcitabine and docetaxel.40 Second, innovative second-line treatment is especially needed for patients who experience recurrence after treatment for metastatic ESFT. In our series, only 28% of initially metastatic patients responded to second-line therapy compared with 67% of initially localized patients. Biologically targeted therapy, such as fenretinide,41 is a particularly attractive novel treatment strategy for recurrent ESFT. Third, the rationale for HDT and optimal myeloablative conditioning remain uncertain. In the absence of a randomized trial comparing HDT consolidation therapy to standard-dose chemotherapy for recurrent ESFT (or comparing different HDT regimens), the role for HDT will remain controversial. Finally, improved initial therapy could reduce disease recurrence and obviate the need for re-treatment. Both the Children’s Oncology Group and EuroEWING 99 are pursuing phase III studies of front-line therapy to improve the outcome for newly diagnosed ESFT.
Even with improved primary treatment for ESFT, recurrent disease remains a significant clinical problem for pediatric and medical oncologists. Our retrospective analysis confirms the poor overall outcome after relapse of ESFT reported by others. We observed improved PFS and OS in patients with prolonged RFI, a response to second-line therapy, initially nonmetastatic disease, and HDT as consolidation therapy. After controlling for RFI and response to second-line therapy, use of HDT seems to be an independent prognostic factor associated with PFS and OS. HDT consolidation for patients who respond to second-line therapy is a promising but unproven approach that may improve the outcome for recurrent ESFT. We concluded that further investigation of HDT, including the determination of the optimal conditioning regimen, is warranted in recurrent ESFT.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported in part by the Rex and Arlene Garrison Student Summer Fellowships from the American Cancer Society and National Institutes of Health grant No. CA-87721.
Presented in abstract form at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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